Sivarajan et al. Infectious Diseases of Poverty (2016) 5:91 DOI 10.1186/s40249-016-0186-x

RESEARCH ARTICLE

Open Access

Clinical and paraclinical profile, and predictors of outcome in 90 cases of scrub typhus, Meghalaya, India Sunuraj Sivarajan1, Siddharudha Shivalli2* , Debomallya Bhuyan1, Michael Mawlong3 and Rittwick Barman1

Abstract Background: India is an integral component of “tsutsugamushi triangle” which depicts a part of the globe endemic to scrub typhus. Owing to frequent outbreaks witnessed in different parts of the country in the recent past, scrub typhus is described as a re-emerging infectious disease in India. The present study aimed to study the clinical and paraclinical profile, complications and predictors of outcome among 90 cases of scrub typhus diagnosed in a hospital of north-eastern India from Sept 2011 to Aug 2012. Methods: A longitudinal study was conducted in a hospital of Meghalaya, India between Sept 2011 and Aug 2012. Diagnosis of scrub typhus was arrived by SD BIOLINE tsutsugamushi (solid phase immunochromatographic assay) rapid diagnostic test for antibodies (IgM, IgG or IgA). Descriptive analyses of age, gender, geographic area, symptoms and signs, treatment, laboratory findings, complications, and outcome were conducted. Relative risk (RR) with 95 % confidence interval (CI) was computed for Multiple Organ Dysfunction Syndrome (MODS) and mortality. Binary logistic regression was applied to the significant correlates (P < 0.05) on univariate analysis to identify the predictors of MODS and mortality in scrub typhus. Results: As many as 662 clinically suspected scrub typhus patients were tested and 90 (13.6 %) were diagnosed to have scrub typhus. Out of 90 patients, 52.2 % (n = 47) were males and their mean (SD) age was 36.29 (13.38) years. Fever of 500 U/L were associated with MODS (P < 0.001) and mortality (P < 0.05). In addition, serum bilirubin >3 mg/dl was also associated with MODS (P < 0.001). On applying binary logistic regression, serum creatinine >1.5 mg/dl was a predictor of MODS (OR: 76.1, 95 % CI: 4.9–1175.6) and mortality (OR: 18.03, 95 % CI: 1.38–235.1). Conclusion: In this study setting, approximately one-seventh (13.6 %) of the acute undifferentiated febrile illness were due to scrub typhus. Systemic complications were common (33.3 %). Serum creatinine >1.5 mg/dl was a predictor of MODS and mortality. (Continued on next page)

* Correspondence: [email protected] 2 Department of Community Medicine, Yenepoya Medical College, Yenepoya University, Mangalore 575018, Karnataka, India Full list of author information is available at the end of the article © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Keywords: Hospital, India, Longitudinal, Multiple Organ Dysfunction Syndrome (MODS), Mortality, Scrub typhus Abbreviations: AKI, Acute Kidney Injury; ALP, Alkaline phosphatase; ALT, Alanine aminotransferase; ARDS, Acute respiratory distress syndrome; AST, Aspartate aminotransferase (AST); CSF, Cerebrospinal fluid; DIC, Disseminated intravascular coagulation; IQR, Inter Quartile range; MODS, Multiple Organ Dysfunction Syndrome; SPSS, Statistical Package for the Social Sciences; WHO, World Health Organization

Multilingual abstracts Please see Additional file 1 for translation of the abstract into the six official working languages of the United Nations. Background Scrub typhus is a vector-borne zoonotic disease caused by Gram-negative bacterium Orientia tsutsugamushi. It is transmitted to humans through the bite of larval trombiculid mite [1, 2]. The infection is maintained in nature transovarially from one generation of mite to the next. Humans are the accidental dead end hosts. After 9–12 days, a typical skin lesion known as eschar is formed at the mite bitten site. It is an acute febrile illness with nonspecific clinical features like high fever, maculopapular rash, lymphadenopathy, headache, and myalgia. India is an integral component of “tsutsugamushi triangle” which depicts a part of the globe endemic to scrub typhus. The “tsutsugamushi triangle” extends from northern Japan and far-eastern Russia in the north, to northern Australia in the south, and to Pakistan in the west [3]. Scrub typhus is one of the important causes of acute undifferentiated febrile illnesses in Asia [4]. High index of suspicion and careful examination for eschar at the bite site is vital for the clinical diagnosis. States like Assam and West Bengal reported the first scrub typhus epidemics in India during World War II. Later scrub typhus was reported in humans and experimental animals exposed in these areas [5]. Owing to frequent outbreaks witnessed in different parts of the country in the recent past, scrub typhus is described as a reemerging infectious disease in India [4, 6–9]. The World Health Organization (WHO) describes scrub typhus as one of the most under diagnosed and underreported febrile illnesses requiring hospitalization. It strongly emphasizes surveillance owing to its relatively high case fatality rate (up to 30 % in untreated patients) and severe underreporting [10]. The present study aimed to describe the clinical and paraclinical profile, complications and predictors of outcome among 90 cases of scrub typhus in a hospital of north-eastern India from Sept 2011 to Aug 2012.

Methods Study setting and design

A longitudinal study was conducted from September 2011 to August 2012 in a hospital, Shillong, Meghalaya, India. This is a 375-bedded multi-specialty hospital in Shillong, the capital of Meghalaya in East Khasi Hills district. The Medicine inpatient facilities include 100 beds. Meghalaya is one of the seven sister states of northeast India with heavy rainfall and agriculture is the main source of economy. East Khasi Hills District is located in the central part of the Meghalaya and covers a total geographical area of 2 748 Sq. Kms. It lies approximately between 25°07” & 25°41” N Lat. and 91°21” & 92°09” E Long [11]. The East Khasi Hills is a typical hilly district with deep gorges and ravines on the southern part. The climate of the district ranges from temperate in the plateau region to warmer tropical and sub-tropical pockets on the Northern and Southern regions. The weather is humid for the major part of the year except for the relatively dry spell usually between December and March [11]. Case definition

Suspected case Acute undifferentiated febrile illness of ≥5 days with/ without eschar. Confirmed case A suspected case of scrub typhus was confirmed by SD Bioline Tsutsugamushi (Standard Diagnostics, Inc., Gyonggi-do, Korea) rapid diagnostic test for IgG, IgM or IgA antibodies [12] and a dramatic response to doxycycline. SD Bioline Tsutsugamushi test is a solid phase immune-chromatographic assay for the rapid, qualitative detection of IgG, IgM or IgA antibodies to Orientia tsutsugamushi in human serum, plasma or whole blood. It has a high sensitivity (99 %), specificity (96 %) and serological agreement (97.5 %) with immunofluorescent assay [13]. A correlation of 97 %, between IgM ELISA and SD Bioline Tsutsugamushi rapid diagnostic test, was reported by Ramyasree A et al. [14] among 100 suspected cases of scrub typhus in India.

Sivarajan et al. Infectious Diseases of Poverty (2016) 5:91

All consecutive patients, aged 18 years and above, presenting with febrile illness were evaluated. Detailed clinical examination, including a careful search for eschar was made in all the patients. All of them were evaluated for other endemic febrile diseases, i.e., malaria, typhoid fever, dengue, leptospirosis, and pneumonia by relevant laboratory tests. Basic laboratory tests like complete blood count, renal function tests (blood urea and serum creatinine), blood glucose, and liver function tests [serum bilirubin (direct and indirect), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) and serum albumin] were done. Other investigations, including chest X-ray, Widal test, blood culture, cerebrospinal fluid (CSF) analysis, and ultrasonography of abdomen were done as indicated. The following criteria were used to define various systemic complications in scrub typhus [15]. 1. Acute Kidney Injury (AKI): Rise of serum creatinine (Scr) of at least 0.3 mg/dl or 50 % higher than baseline within a 24–48-h period or a reduction in urine output to 0.5 mL/kg per hour for longer than 6 h. 2. Acute hepatitis: Elevation of serum transaminases more than 6 times the normal upper limit. 3. Acute respiratory distress syndrome (ARDS): Acute onset of non-cardiogenic pulmonary edema manifesting with bilateral alveolar or interstitial infiltrates on chest radiograph and PaO2/FIO2 ≤ 200 mmHg on arterial blood gas analysis. 4. Pneumonitis: Acute onset of non-cardiogenic pulmonary edema manifesting with unilateral or bilateral alveolar or interstitial infiltrates on chest radiograph and PaO2/FIO2 > 200 mmHg on arterial blood gas analysis. 5. Disseminated intravascular coagulation (DIC): Prolongation of PT and/or aPTT; platelet counts 100 000/μl3, or a rapid decline in platelet numbers over 24 h; the presence of schistocytes (fragmented red cells) in the blood smear; and elevated levels of fibrin degradation products (FDPs). 6. Pancreatitis: Acute onset of clinical symptoms such as abdominal pain, vomiting, guarding/ tenderness associated with elevation of serum amylase/ lipase >3 times upper limit of normal. 7. Septic shock: Systolic blood pressure of 1.5 mg/dl was a predictor of MODS (OR: 76.1, 95 % CI: 4.9–1175.6) and mortality (OR: 18.03, 95 % CI: 1.38–235.1). The ARDS taskforce published the Berlin definition of ARDS in June 2012 [17]. This study was started in Sept 2011 and hence, we did not use these criteria for ARDS. According Berlin definition, pneumonitis and ARDS used in this study are classified as mild and moderate ARDS, respectively [17]. However, even with the Berlin definition of ARDS, serum creatinine >1.5 mg/dl was a predictor of MODS (OR: 35.32, 95 % CI: 4.2–299.7) and mortality (OR: 50.3, 95 % CI: 3.4–734.8).

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Table 2 Laboratory findings of patients with scrub typhus in a tertiary care hospital of Meghalaya, India, Sept 2011–Aug 2012 (n = 90) Laboratory parameter

N

%

Leucocytosis (>12 000/μl)

23

25

Leucopoenia (40 IU

85

94

Alkaline phosphatase >130 IU/L

74

82

Serum creatinine >1.6 mg/dl

13

14

Serum albumin < 3 g%

21

23

Thrombocytopenia (per μl)

Discussion Key findings

In this study setting, 13.6 % of acute undifferentiated febrile illness was attributed to scrub typhus. One third (n = 30) of the patients developed at least one systemic complication. MODS was seen in 14.4 % (n = 13) and 38.5 % of patients with MODS died, and the overall case fatality rate was 5.15 %. Serum creatinine >1.5 mg/dl was a predictor of MODS (OR: 76.1, 95 % CI: 4.9– 1175.6) and mortality (OR: 18.03, 95 % CI: 1.38–235.1). Interpretation

Although many states of India have reported the disease outbreak, paucity of data hinders further research on scrub typhus. This longitudinal study was an attempt to explore the predictors of complications and outcome in

scrub typhus. Corroborating with other studies [6, 10, 15, 18–22], the present one also reaffirms that scrub typhus commonly presents with non-specific symptoms like acute onset of fever with myalgia, breathlessness, cough, nausea, vomiting, headache etc. It is difficult to differentiate scrub typhus from other co-endemic diseases like malaria, dengue, and leptospirosis. Therefore, a high index of clinical suspicion, exploring the history of environmental exposure, and vigilant search for the eschar are crucial for diagnosis. Seasonal occurrence of scrub typhus is seen and it varies with the climate in different countries. Epidemic period is influenced by the activities of the infected mite and often occurs during the rainy season [23, 24]. However, similar to our study, outbreaks have been reported during the cooler season or post monsoon, in India [9, 25–27]. In the cooler months, there is an increase in secondary shrub vegetation which in turn favors the growth of the vector. In the same season, farmers are involved in harvesting activity in the fields, where they are exposed to the bites of larval mites [28, 29]. Therefore, intensified health education activities are needed in the rainy and post monsoon sessions to cut down the transmission. Targeted preventive interventions like personal protection are to be canvassed among the high risk groups like farmers and those involved in collecting firewood from jungle. This study and other studies conducted in India [5, 9] and Asia [19, 20] have shown lower positivity for the eschar (8–15 %) in scrub typhus. Indigenous patients of typhus endemic areas regularly tend to have less severe illness, often without rash or eschar [21]. Whether this is due to past exposure to the organism, variation in strain type or other factors needs to be explored.

Table 3 Salient features of patients with scrub typhus and Multiple Organ Dysfunction Syndrome (MODS) in a hospital of Meghalaya, India, Sept 2011–Aug 2012 (n = 13) No

Age (years)

Sex

TC†

Plt/mm3††

Hypotension/shock

ARDS§

1

24

M

15 800

160 000

Hypotension



2

24

M

16 200

45,000

3

25

M

12 500

19 000

4

25

M

13 300

141 000

5

25

F

20 900

120 000

6

26

M

4 600

16 200





Recovered

7

27

M

15 700

24 000





Recovered

8

29

F

15 100

28 000

Hypotension







Expired

9

42

F

37 000

215 000







Expired

10

44

F

10 600

27 000





Expired

11

46

F

12 000

72 000





Recovered

12

70

F

13 300

80 000





Expired

13

76

F

16 200

45 000





Recovered



TC total count,

††

Meningitis ✓



Acute hepatitis

AKI¶

Outcome





Recovered



Recovered



Recovered

✓ ✓





✓ ✓ ✓

Recovered Expired

Plt/mm3 platelets/cubic millimeter, §ARDS Acute Respiratory Distress Syndrome, ¶AKI Acute Kidney Injury

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Table 4 Cerebrospinal fluid (CSF) findings among patients with scrub typhus meningitis in a tertiary care hospital of Meghalaya, India, Sept 2011–Aug 2012 (n = 5) No

Age (years)

Sex

Total count (/mm3)

Polymorphs (%)

Lymphocytes (%)

Protein (mg/dl)

Sugar (mg/dl)

RBC (mm3)a

ADAb

(U/L)

1

24

Male

220

1

99

122

56

50

5.0

2

25

Female

91

2

89

155

25



7.8

3

44

Female

101

9

89

93

17

30

10.0

4

53

Female

11

3

8

143

25



11.0

5

76

Female

111

4

96

113

63



8.8

RBC red blood cell, bADA adenosine deaminase

a

Therefore, in the Indian context absence of eschar does not rule out the diagnosis. As observed in our study and by others [9, 22, 30] elevated serum tarnsaminase levels and thrombocytopenia appears to be a consistent paraclinical feature in scrub typhus. In a study by Varghese GM et al. (n = 50), a combination of elevated transaminases, thrombocytopenia and leukocytosis displayed 80 % specificity and positive predictive value for scrub typhus diagnosis [9]. This could be very useful to primary care physicians who may not have immediate access to confirmatory tests. However, this association needs to be further validated by analytical epidemiological studies on larger samples. The present study like some others [27, 30–32] suggest that systemic complications are common in scrub typhus. Both agent and the host factors are decisive for the occurrence of complications. Orientia tsutsugamushi has more than 20 antigenically distinct regionally distributed serotypes and some strains seem to have higher virulence [31]. Host factors like older age, co-morbidities, paraclinical features on admission and delayed onset of treatment seem to contribute to the disease severity and complications. Occurrence of systemic complications like shock, acute renal failure, meningitis, and MODS are associated with a higher mortality [32]. A wide range of case fatality rate for scrub typhus (5–30 %) is reported in

India [4, 9, 32, 33] and across the globe [21, 34]. However, a decreasing trend in the mortality is evident over the years [32, 33]. It could be attributed to increased awareness, early seeking of healthcare, timely initiation of antibiotic treatment and/or possible lower virulent strain of tsutsugamushi in the area. In the present study, gender wise (women vs. men) differences in MODS (16.3 % vs. 12.8 %) and fatality rate (11.6 % vs. 0 %) were statistically not significant (P > 0.05). Whether it was a serendipitous finding or due to biological susceptibility or social factors such as ignorance and delay in seeking care, need to be investigated. Similar to our finding, creatinine >1/4 mg/dl was an independent predictor of mortality in scrub typhus in a study from southern India [8]. Fever of >12 days, presence of eschar, ICU admission, shock needing ionotropes, CNS dysfunction etc. have also been proven to be predictors of mortality [5, 14, 35]. These give valuable hints to the impending fatal outcome and may help the clinicians to initiate the intensive management. Although doxycycline is the drug of choice for scrub typhus [36, 37], clinical failure and resistance is reported [38, 39]. A meta-analysis by Panpanich R et al. [40] reveals the paucity of high quality evidence about the antibiotics for scrub typhus. However, the existing evidence suggests that there is no obvious differences

Table 5 Relative risks (RR) for Multiple Organ Dysfunction Syndrome (MODS) and mortality among patients with scrub typhus in a hospital of Meghalaya, India, Sept 2011–Aug 2012 (n = 90) Study variable

MODS (n = 13) RR

95 % CI

p

RR

95 % CI

p

Gender (female vs. male)

1.3

0.46–3.5

0.637

12

0.68–210.8

0.637

Presence of eschar

2.4

0.79–7.28

0.122

2.0

0.25–16.17

0.515

Fever (7 days)

2.4

0.34–17.1

0.38

2.32

0.14–39.8

0.562

Occupation (farmer / labourer vs. others)

0.45

0.13–1.52

0.199

1.0

0.17–5.69

1.00

Age (≥60 years vs. 3 mg/dl

16.16

5.97–43.7

Clinical and paraclinical profile, and predictors of outcome in 90 cases of scrub typhus, Meghalaya, India.

India is an integral component of "tsutsugamushi triangle" which depicts a part of the globe endemic to scrub typhus. Owing to frequent outbreaks witn...
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